Abstract:

This invention relates to novel acetamide derivatives that are found to be
potent modulators of ion channels, in particular potassium channels and
chloride channels, and, as such, are valuable candidates for the
treatment of diseases or disorders as diverse as those which are
responsive to the modulation of potassium channels.

Claims:

1-9. (canceled)

10. An acetamide derivative of Formula I ##STR00008## a stereoisomer or a
mixture of its stereoisomers, or a pharmaceutically-acceptable addition
salt thereof, whereinR1 represents a tetrazolyl, an
N-hydroxy-carbamimidoyl or a 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl
group;R2 represents halo, trifluoromethyl or phenyl, which phenyl
may optionally be substituted one or two times with halo,
trifluoromethyl, trifluoromethoxy and/or N,N-dialkylsulfamoyl; andR3
and R4, independently of each other, represent hydrogen, halo or
trifluoromethyl hydroxy, alkylsulfonyl or SO2NR'R'', wherein R' and
R'' represents hydrogen or alkyl, or R' and R'', together with the N-atom
to which they are attached, form a heterocyclic ring selected from
piperidine, piperazine and morpholine.

11. The acetamide derivative of claim 10, a stereoisomer or a mixture of
its stereoisomers, or a pharmaceutically-acceptable addition salt
thereof, wherein R1 represents a tetrazolyl, an
N-hydroxy-carbamimidoyl or a 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl
group.

12. The acetamide derivative of claim 10, a stereoisomer or a mixture of
its stereoisomers, or a pharmaceutically-acceptable addition salt
thereof, wherein R2 represents halo, trifluoromethyl or phenyl,
which phenyl may optionally be substituted one or two times with halo,
trifluoromethyl, trifluoromethoxy and/or N,N-dialkylsulfamoyl.

13. The acetamide derivative of claim 10, a stereoisomer or a mixture of
its stereoisomers, or a pharmaceutically-acceptable addition salt
thereof, wherein R3 and R4, independently of each other,
represent hydrogen, halo, trifluoromethyl, hydroxy, alkylsulfonyl or
SO2NR'R'', wherein R' and R'' represents hydrogen or alkyl, or R'
and R'', together with the N-atom to which they are attached, form a
heterocyclic ring selected from piperidine, piperazine and morpholine.

15. A pharmaceutical composition comprising a therapeutically effective
amount of the acetamide derivative of claim 10, a stereoisomer or a
mixture of its stereoisomers, or a pharmaceutically-acceptable addition
salt thereof, together with one or more adjuvants, excipients, carriers
and/or diluents.

16. A method of treatment, prevention or alleviation of a disease or a
disorder or a condition of a living animal body, including a human, which
disorder, disease or condition is responsive to modulation of ion
channels, which method comprises the step of administering to such a
living animal body in need thereof, a therapeutically effective amount of
the acetamide derivative according to claim 10, a stereoisomer or a
mixture of its stereoisomers, or a pharmaceutically-acceptable addition
salt thereof.

Description:

TECHNICAL FIELD

[0001]This invention relates to novel acetamide derivatives that are found
to be potent modulators of ion channels, in particular potassium channels
and chloride channels, and, as such, are valuable candidates for the
treatment of diseases or disorders as diverse as those which are
responsive to the modulation of potassium channels.

BACKGROUND ART

[0002]Ion channels are cellular proteins that regulate the flow of ions
through cellular membranes of all cells and are classified by their
selective permeability to the different of ions (potassium, chloride,
sodium etc.). Potassium channels, which represent the largest and most
diverse sub-group of ion channels, selectively pass potassium ions and,
doing so, they principally regulate the resting membrane potential of the
cell and/or modulate their level of excitation.

[0003]Dysfunction of potassium channels, as well as other ion channels,
generates loss of cellular control resulting in altered physiological
functioning and disease conditions. Ion channel blockers and openers, by
their ability to modulate ion channel function and/or regain ion channel
activity in acquired or inherited channelopathies, are being used in the
pharmacological treatment of a wide range of pathological diseases and
have the potential to address an even wider variety of therapeutic
indications. For instance, the primary indications for potassium channel
openers encompass conditions as diverse as diabetes, arterial
hypertension, cardiovascular diseases, urinary incontinence, atrial
fibrillation, epilepsy, pain, and cancer.

[0004]Among the large number of potassium channel types, the
large-conductance calcium-activated potassium channel subtype is an
obvious site for pharmacological intervention and for the development of
new potassium channel modulators. Their physiological role has been
especially studied in the nervous system, where they are key regulators
of neuronal excitability and of neurotransmitter release, and in smooth
muscle, where they are crucial in modulating the tone of vascular,
broncho-tracheal, urethral, uterine or gastro-intestinal musculature.

[0005]Given these implications, small agents with BK-opening properties
could have a potentially powerful influence in the modulation and control
of numerous consequences of muscular and neuronal hyperexcitability, such
as asthma, urinary incontinence and bladder spasm, gastroenteric
hypermotility, psychoses, post-stroke neuroprotection, convulsions,
anxiety and pain. As far as the cardiovascular system is concerned, the
physiological function of these ion channels represents a fundamental
steady state mechanism, modulating vessel depolarisation,
vasoconstriction and increases of intravascular pressure, and the
development of selective activators of BK channels is seen as a potential
pharmacotherapy of vascular diseases, including hypertension, erectile
dysfunction, coronary diseases and vascular complications associated with
diabetes or hypercholesterolemia.

[0006]Chloride channels serve a wide variety of specific cellular
functions and contribute to the normal function of i.a. skeletal and
smooth muscle cells. Chloride channels are probably found in every cell,
from bacteria to mammals. Their physiological tasks range from cell
volume regulation to stabilization of the membrane potential,
transepithelial or transcellular transport and acidification of
intracellular organelles.

[0007]WO 2007/044724 describes certain N-tetrazolylphenyl carboxamide
derivatives useful as PIM-1 and PIM-3 protein kinase inhibitors. However,
the acetamide derivatives of the present invention are not described, and
their use as potassium channel modulators certainly not suggested.

SUMMARY OF THE INVENTION

[0008]Is an object of the invention to provide novel acetamide derivatives
useful as ion channel modulators. The acetamide derivatives of the
invention may be characterised by Formula I

##STR00001##

[0009]a stereoisomer or a mixture of its stereoisomers, or a
pharmaceutically-acceptable addition salt thereof, wherein

[0010]R1 represents a tetrazolyl, an N-hydroxy-carbamimidoyl or a
5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl group;

[0011]R2 represents halo, trifluoromethyl or phenyl, which phenyl may
optionally be substituted one or two times with halo, trifluoromethyl,
trifluoromethoxy and/or N,N-dialkylsulfamoyl; and

[0012]R3 and R4, independently of each other, represent
hydrogen, halo or trifluoromethyl hydroxy, alkylsulfonyl or
SO2NR'R'', wherein R' and R'' represents hydrogen or alkyl, or R'
and R'', together with the N-atom to which they are attached, form a
heterocyclic ring selected from piperidine, piperazine and morpholine.

[0013]In another aspect the invention provides pharmaceutical compositions
comprising a therapeutically effective amount of an acetamide derivative
of the invention.

[0014]In a third aspect the invention relates to the use of the acetamide
derivatives of the invention for the manufacture of pharmaceutical
compositions.

[0015]In a further aspect the invention provides a method of treatment,
prevention or alleviation of a disease or a disorder or a condition of a
living animal body, including a human, which disorder, disease or
condition is responsive to modulation of ion channels, which method
comprises the step of administering to such a living animal body in need
thereof, a therapeutically effective amount of the acetamide derivative
of the invention.

[0016]Other objects of the invention will be apparent to the person
skilled in the art from the following detailed description and examples.

DETAILED DISCLOSURE OF THE INVENTION

[0017]In its first aspect the invention provides novel acetamide
derivatives of Formula I

##STR00002##

[0018]a stereoisomer or a mixture of its stereoisomers, or a
pharmaceutically-acceptable addition salt thereof, wherein

[0019]R1 represents a tetrazolyl, an N-hydroxy-carbamimidoyl or a
5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl group;

[0020]R2 represents halo, trifluoromethyl or phenyl, which phenyl may
optionally be substituted one or two times with halo, trifluoromethyl,
trifluoromethoxy and/or N,N-dialkylsulfamoyl; and

[0021]R3 and R4, independently of each other, represent
hydrogen, halo or trifluoromethyl hydroxy, alkylsulfonyl or
SO2NR'R'', wherein R' and R'' represents hydrogen or alkyl, or R'
and R'', together with the N-atom to which they are attached, form a
heterocyclic ring selected from piperidine, piperazine and morpholine;

[0022]provided, however, if R1 represents tetrazolyl, R2
represents chloro, and one of R3 and R4 represents hydrogen or
bromo; then the other of R3 and R4 does not represent hydrogen.

[0023]In a more preferred embodiment the acetamide derivative of the
invention is a compound of Formula Ia

##STR00003##

[0024]a stereoisomer or a mixture of its stereoisomers, or a
pharmaceutically-acceptable addition salt thereof, wherein R1,
R2, R3 and R4 are as defined above.

[0025]In another more preferred embodiment the acetamide derivative of the
invention is a compound of Formula Ib

##STR00004##

[0026]a stereoisomer or a mixture of its stereoisomers, or a
pharmaceutically-acceptable addition salt thereof, wherein R1,
R2, R3 and R4 are as defined above.

[0027]In an even more preferred embodiment the acetamide derivative of the
invention is a compound of Formula Ib, wherein

[0028]R1 and R2 are as defined above; and

[0029]R3 and R4, independently of each other, represent halo, in
particular fluoro or chloro, or trifluoromethyl.

[0030]In a third more preferred embodiment the acetamide derivative of the
invention is a compound of Formula Ic

##STR00005##

[0031]a stereoisomer or a mixture of its stereoisomers, or a
pharmaceutically-acceptable addition salt thereof, wherein

[0032]R1 and R2 are as defined above; and

[0033]R3 represents halo, in particular chloro, or trifluoromethyl.

[0034]In an even more preferred embodiment the acetamide derivative of the
invention is a compound of Formula Ic, wherein R3 represents halo,
and in particular chloro.

[0035]In another preferred embodiment the acetamide derivative of the
invention is a compound of Formula I, Ia, Ab or Ic, or a
pharmaceutically-acceptable addition salt thereof, wherein R1
represents a tetrazolyl, an N-hydroxy-carbamimidoyl or a
5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl group.

[0036]In a more preferred embodiment R1 represents a tetrazolyl
group, in particular a 1H-tetrazol-5-yl group.

[0037]In another more preferred embodiment R1 represents an
N-hydroxy-carbamimidoyl group.

[0038]In a third more preferred embodiment R1 represents a
5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl group.

[0039]In a third preferred embodiment the acetamide derivative of the
invention is a compound of Formula I, Ia, Ab or Ic, or a
pharmaceutically-acceptable addition salt thereof, wherein R2
represents halo, trifluoromethyl or phenyl, which phenyl may optionally
be substituted one or two times with halo, trifluoromethyl,
trifluoromethoxy and/or N,N-dialkylsulfamoyl.

[0040]In a more preferred embodiment R2 represents halo, in
particular chloro or bromo, or phenyl, which phenyl may optionally be
substituted one or two times with halo, in particular fluoro,
trifluoromethyl, trifluoromethoxy and/or N,N-dialkylsulfamoyl.

[0041]In an even more preferred embodiment R2 represents halo or
trifluoromethyl.

[0042]In another more preferred embodiment R2 represents halo, and in
particular chloro or bromo.

[0043]In a third more preferred embodiment R2 represents phenyl,
which phenyl may optionally be substituted with halo, in particular
fluoro, trifluoromethyl, trifluoromethoxy or N,N-dialkylsulfamoyl.

[0044]In an even more preferred embodiment R2 represents phenyl.

[0045]In a fourth more preferred embodiment R2 represents a phenyl
group substituted with halo, in particular fluoro, trifluoromethyl,
trifluoromethoxy or N,N-dialkylsulfamoyl.

[0046]In an even more preferred embodiment R2 represents a phenyl
group substituted with halo, in particular fluoro.

[0047]In a fifth more preferred embodiment R2 represents a phenyl
group substituted with trifluoromethyl.

[0048]In a sixth more preferred embodiment R2 represents a phenyl
group substituted with trifluoromethoxy.

[0049]In a seventh more preferred embodiment R2 represents a phenyl
group substituted with N,N-dialkylsulfamoyl, in particular
N,N-dimethylsulfamoyl.

[0050]In a fourth preferred embodiment the acetamide derivative of the
invention is a compound of Formula I, Ia, Ab or Ic, or a
pharmaceutically-acceptable addition salt thereof, wherein R3 and
R4, independently of each other, represent hydrogen, halo,
trifluoromethyl, hydroxy, alkylsulfonyl or SO2NR'R'', wherein R' and
R'' represents hydrogen or alkyl, or R' and R'', together with the N-atom
to which they are attached, form a heterocyclic ring selected from
piperidine, piperazine and morpholine.

[0051]In a more preferred embodiment R3 and R4, independently of
each other, represent hydrogen, halo, trifluoromethyl, hydroxy,
alkylsulfonyl or SO2NR'R'', wherein R' and R'' together with the
N-atom to which they are attached, form a piperidine ring.

[0052]R3 and R4, independently of each other, represent
hydrogen, halo, in particular fluoro or chloro, or trifluoromethyl.

[0053]In a more preferred embodiment R3 and R4 both represent
halo, in particular fluoro or chloro, or trifluoromethyl.

[0054]In another more preferred embodiment R3 and R4 both
represent halo, in particular fluoro or chloro.

[0055]In a third more preferred embodiment R3 and R4 both
represent trifluoromethyl.

[0068]Any combination of two or more of the embodiments described herein
is considered within the scope of the present invention.

Definition of Substituents

[0069]In the context of this invention halo represents fluoro, chloro,
bromo or iodo.

[0070]In the context of this invention an alkyl group designates a
univalent saturated, straight or branched hydrocarbon chain. The
hydrocarbon chain preferably contain of from one to eighteen carbon atoms
(C1-18-alkyl), more preferred of from one to six carbon atoms
(C1-6-alkyl; lower alkyl), including pentyl, isopentyl, neopentyl,
tertiary pentyl, hexyl and isohexyl. In a preferred embodiment alkyl
represents a C1-4-alkyl group, including butyl, isobutyl, secondary
butyl, and tertiary butyl. In another preferred embodiment of this
invention alkyl represents a C1-3-alkyl group, which may in
particular be methyl, ethyl, propyl or isopropyl.

Pharmaceutically Acceptable Salts

[0071]The acetamide derivatives of the invention may be provided in any
form suitable for the intended administration. Suitable forms include
pharmaceutically (i.e. physiologically) acceptable salts, and pre- or
prodrug forms of the acetamide derivative of the invention.

[0072]Examples of pharmaceutically acceptable addition salts include,
without limitation, the non-toxic inorganic and organic acid addition
salts such as the hydrochloride, the hydrobromide, the nitrate, the
perchlorate, the phosphate, the sulphate, the formate, the acetate, the
aconate, the ascorbate, the benzenesulphonate, the benzoate, the
cinnamate, the citrate, the embonate, the enantate, the fumarate, the
glutamate, the glycolate, the lactate, the maleate, the malonate, the
mandelate, the methanesulphonate, the naphthalene-2-sulphonate derived,
the phthalate, the salicylate, the sorbate, the stearate, the succinate,
the tartrate, the toluene-p-sulphonate, and the like. Such salts may be
formed by procedures well known and described in the art.

[0073]Examples of pharmaceutically acceptable cationic salts of an
acetamide derivative of the invention include, without limitation, the
sodium, the potassium, the calcium, the magnesium, the lithium, and the
ammonium salt, and the like, of an acetamide derivative of the invention
containing an anionic group. Such cationic salts may be formed by
procedures well known and described in the art.

Steric Isomers

[0074]It will be appreciated by those skilled in the art that the
compounds of the present invention may exist in different stereoisomeric
forms, including enantiomers, diastereomers, as well as geometric isomers
(cis-trans isomers). The invention includes all such isomers and any
mixtures thereof including racemic mixtures.

[0075]Racemic forms can be resolved into the optical antipodes by known
methods and techniques. One way of resolving racemates into the optical
antipodes is based upon chromatography on an optical active matrix.
Racemic compounds of the present invention can thus be resolved into
their optical antipodes, e.g., by fractional crystallisation of D- or
L-(tartrates, mandelates, or camphorsulphonate) salts for example.

[0076]Additional methods for the resolving the optical isomers are known
in the art. Such methods include those described by Jaques J, Collet A, &
Wilen S in "Enantiomers. Racemates, and Resolutions", John Wiley and
Sons, New York (1981). Optical active compounds can also be prepared from
optically active starting materials or intermediates.

Methods of Preparation

[0077]The compounds according to the invention may be prepared by
conventional methods for chemical synthesis, e.g. those described in the
working examples.

Biological Activity

[0078]The acetamide derivatives of the invention have been found to
possess ion channel modulating activity, and in particular potassium
channel activating activity and chloride channel blocking activity, as
measured by standard electrophysiological methods. Due to their activity
at the potassium and chloride channels, the acetamide derivatives of the
invention are considered useful for the treatment of a wide range of
diseases and conditions.

[0080]In a more preferred embodiment, the acetamide derivatives of the
invention are considered useful for the treatment, prevention or
alleviation of a respiratory disease, urinary incontinence, erectile
dysfunction, anxiety, epilepsy, psychosis, schizophrenia, bipolar
disorder, depression, amyotrophic lateral sclerosis (ALS), Parkinson's
disease or pain.

[0081]In another more preferred embodiment, the acetamide derivatives of
the invention are considered useful for the treatment, prevention or
alleviation of psychosis, schizophrenia, bipolar disorder, depression,
epilepsy, Parkinson's disease or pain.

[0082]In a third more preferred embodiment, the acetamide derivatives of
the invention are considered useful for the treatment, prevention or
alleviation of pain, mild or moderate or severe pain, pain of acute,
chronic or recurrent character, pain caused by migraine, postoperative
pain, phantom limb pain, inflammatory pain, neuropathic pain, chronic
headache, central pain, pain related to diabetic neuropathy, to post
therapeutic neuralgia, or to peripheral nerve injury.

[0084]In a fifth more preferred embodiment, the acetamide derivatives of
the invention are considered useful for the treatment, prevention or
alleviation of cardiac ischemia, ischemic heart disease, hypertrophic
heart, cardiomyopathy or failing heart.

[0085]In a sixth more preferred embodiment, the compounds of the invention
are considered useful for the treatment, prevention or alleviation of a
cardiovascular disease. In a more preferred embodiment the cardiovascular
disease is atherosclerosis, ischemia/reperfusion, hypertension,
restenosis, arterial inflammation, myocardial ischaemia or ischaemic
heart disease.

[0086]In a seventh more preferred embodiment, the acetamide derivatives of
the invention are considered useful for the treatment, prevention or
alleviation of cardiac arrhythmia, atrial fibrillation and/or ventricular
tachyarrhythmia.

[0087]In an eighth more preferred embodiment, the compounds of the
invention are considered useful for obtaining preconditioning of the
heart. Preconditioning, which includes ischemic preconditioning and
myocardial preconditioning, describes short periods of ischemic events
before initiation of a long lasting ischemia. The compounds of the
invention are believed having an effect similar to preconditioning
obtained by such ischemic events. Preconditioning protects against later
tissue damage resulting from the long lasting ischemic events.

[0088]In a ninth more preferred embodiment, the acetamide derivatives of
the invention are considered useful for the treatment, prevention or
alleviation of schizophrenia, depression or Parkinson's disease.

[0089]In a tenth more preferred embodiment, the compounds of the invention
are considered useful for the treatment, prevention or alleviation of an
obstructive or inflammatory airway disease. In a more preferred
embodiment the obstructive or inflammatory airway disease is an airway
hyperreactivity, a pneumoconiosis such as aluminosis, anthracosis,
asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and
byssinosis, a chronic obstructive pulmonary disease (COPD), bronchitis,
excerbation of airways hyperreactivity or cystic fibrosis.

[0091]In an eleventh more preferred embodiment, the acetamide derivatives
of the invention are considered useful for the treatment, prevention or
alleviation of a sexual dysfunction, incl. male sexual dysfunction and
female sexual dysfunction, and incl. male erectile dysfunction.

[0092]In an even more preferred embodiment the acetamide derivative of the
invention may be co-administered with a phosphodiesterase inhibitor, in
particular a phosphodiesterase 5 (PDE5) inhibitor, e.g. sildenafil,
tadalafil, vardenafil and dipyridamole, or with an agent that potentiates
endothelium-derived hyperpolarizing factor-mediated responses, in
particular calcium dobesilate or similar 2,5-dihydroxybenzenesulfonate
analogs.

[0093]In a most preferred embodiment the acetamide derivative of the
invention is used in a combination therapy together with sildenafil,
tadalafil, vardenafil or calcium dobesilate.

[0095]The acetamide derivatives of the invention are considered particular
useful for the treatment of a disease, disorder or condition that is
responsive to reduction of intraocular pressure, such as ocular
hypertension, open-angle glaucoma, chronic open-angle glaucoma,
angle-closure glaucoma and ciliary injection caused by angle-closure
glaucoma.

[0096]It is at present contemplated that a suitable dosage of the active
pharmaceutical ingredient (API) is within the range of from about 0.1 to
about 1000 mg API per day, more preferred of from about 10 to about 500
mg API per day, most preferred of from about 30 to about 100 mg API per
day, dependent, however, upon the exact mode of administration, the form
in which it is administered, the indication considered, the subject and
in particular the body weight of the subject involved, and further the
preference and experience of the physician or veterinarian in charge.

[0097]Preferred acetamide derivatives of the invention show a biological
activity in the sub-micromolar and micromolar range, i.e. of from below 1
to about 100 μM.

Pharmaceutical Compositions

[0098]In another aspect the invention provides novel pharmaceutical
compositions comprising a therapeutically effective amount of an
acetamide derivative of the invention.

[0099]While an acetamide derivative of the invention for use in therapy
may be administered in the form of the raw chemical compound, it is
preferred to introduce the active ingredient, optionally in the form of a
physiologically acceptable salt, in a pharmaceutical composition together
with one or more adjuvants, excipients, carriers, buffers, diluents,
and/or other customary pharmaceutical auxiliaries.

[0100]In a preferred embodiment, the invention provides pharmaceutical
compositions comprising the acetamide derivative of the invention
together with one or more pharmaceutically acceptable carriers therefore,
and, optionally, other therapeutic and/or prophylactic ingredients, know
and used in the art. The carrier(s) must be "acceptable" in the sense of
being compatible with the other ingredients of the formulation and not
harmful to the recipient thereof.

[0101]The pharmaceutical composition of the invention may be administered
by any convenient route, which suits the desired therapy. Preferred
routes of administration include oral administration, in particular in
tablet, in capsule, in drage, in powder, or in liquid form, and
parenteral administration, in particular cutaneous, subcutaneous,
intramuscular, or intravenous injection. The pharmaceutical composition
of the invention can be manufactured by any person skilled in the art, by
use of standard methods and conventional techniques, appropriate to the
desired formulation. When desired, compositions adapted to give sustained
release of the active ingredient may be employed.

[0102]Further details on techniques for formulation and administration may
be found in the latest edition of Remington's Pharmaceutical Sciences
(Maack Publishing Co., Easton, Pa.).

[0103]The actual dosage depends on the nature and severity of the disease
being treated, and is within the discretion of the physician, and may be
varied by titration of the dosage to the particular circumstances of this
invention to produce the desired therapeutic effect. However, it is
presently contemplated that pharmaceutical compositions containing of
from about 0.1 to about 500 mg of active ingredient per individual dose,
preferably of from about 1 to about 100 mg, most preferred of from about
1 to about 10 mg, are suitable for therapeutic treatments.

[0104]The active ingredient may be administered in one or several doses
per day. A satisfactory result can, in certain instances, be obtained at
a dosage as low as 0.1 μg/kg i.v. and 1 μg/kg p.o. The upper limit
of the dosage range is presently considered to be about 10 mg/kg i.v. and
100 mg/kg p.o. Preferred ranges are from about 0.1 μg/kg to about 10
mg/kg/day i.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.

Pharmaceutical Kits of Parts

[0105]According to the invention there is also provided a kit of parts
comprising at least two separate unit dosage forms (A) and (B):

[0109](C) instructions for the simultaneous, sequential or separate
administration of the acetamide derivative of A, and the
phosphodiesterase inhibitor of B1, or an agent that potentiates
endothelium-derived hyperpolarizing factor-mediated responses of B2, to a
patient in need thereof.

[0110]In a more preferred embodiment the phosphodiesterase inhibitor for
use according to the invention (B1) is a phosphodiesterase 5 (PDE5)
inhibitor, and in an even more preferred embodiment the phosphodiesterase
inhibitor for use according to the invention is sildenafil, tadalafil or
vardenafil.

[0111]In another more preferred embodiment the agent that potentiates
endothelium-derived hyperpolarizing factor-mediated responses for use
according to the invention (B2) is calcium dobesilate.

[0112]The acetamide derivative of the invention and the phosphodiesterase
inhibitor or the agent that potentiates endothelium-derived
hyperpolarizing factor-mediated responses for use according to the
invention may preferably be provided in a form that is suitable for
administration in conjunction with the other. This is intended to include
instances where one or the other of two formulations may be administered
(optionally repeatedly) prior to, after, and/or at the same time as
administration with the other component.

[0113]Also, the acetamide derivative of the invention and the
phosphodiesterase inhibitor or the agent that potentiates
endothelium-derived hyperpolarizing factor-mediated responses for use
according to the invention may be administered in a combined form, or
separately or separately and sequentially, wherein the sequential
administration is close in time or remote in time. This may in particular
include that two formulations are administered (optionally repeatedly)
sufficiently closely in time for there to be a beneficial effect for the
patient, that is greater over the course of the treatment of the relevant
condition than if either of the two formulations are administered
(optionally repeatedly) alone, in the absence of the other formulation,
over the same course of treatment. Determination of whether a combination
provides a greater beneficial effect in respect of, and over the course
of treatment of, a particular condition, will depend upon the condition
to be treated or prevented, but may be achieved routinely by the person
skilled in the art.

[0114]When used in this context, the terms "administered simultaneously"
and "administered at the same time as" include that individual doses of
the positive allosteric nicotine receptor modulator and the cognitive
enhancer are administered within 48 hours, e.g. 24 hours, of each other.

[0115]Bringing the two components into association with each other,
includes that components (A) and (B) may be provided as separate
formulations (i.e. independently of one another), which are subsequently
brought together for use in conjunction with each other in combination
therapy; or packaged and presented together as separate components of a
"combination pack" for use in conjunction with each other in combination
therapy.

Methods of Therapy

[0116]In another aspect the invention provides a method of treatment,
prevention or alleviation of a disease, disorder or condition of a living
animal body, including a human, which disorder, disease or condition is
responsive to modulation of an ion channel, and in particular a potassium
channel or a chloride channel, which method comprises the step of
administering to such a living animal body in need thereof, a
therapeutically effective amount a compound capable of activating the
potassium channel, or a pharmaceutically-acceptable addition salt
thereof.

[0117]The preferred medical indications contemplated according to the
invention are those stated above.

[0118]It is at present contemplated that a suitable dosage of the active
pharmaceutical ingredient (API) is within the range of from about 0.1 to
about 1000 mg API per day, more preferred of from about 1 to about 500 mg
API per day, most preferred of from about 1 to about 100 mg API per day,
dependent, however, upon the exact mode of administration, the form in
which it is administered, the indication considered, the subject and in
particular the body weight of the subject involved, and further the
preference and experience of the physician or veterinarian in charge.

[0120]The invention is further illustrated with reference to the following
examples, which are not intended to be in any way limiting to the scope
of the invention as claimed.

Example 1

Preparatory Example

General Experimental Procedure

##STR00006##

[0122]The synthetic pathway of the acetamide compounds of the invention
involves amide formation by coupling a suitably-substituted phenylacetic
acid (A, X═OH) with an ortho-substituted aniline (B) in presence of
EDC (1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride) or
coupling a suitably-substituted phenylacetylchloride (A, X═Cl),
commercially-available or prepared from the corresponding commercial
phenylacetic acids by treatment with thionyl chloride, with an
ortho-substituted aniline (B). When the aniline (B) was not
commercially-available it was synthesised either as described in e.g. WO
98/47879 and in Valgeirsson et al. in Journal of Medicinal Chemistry 2004
47 (27) 6948-6957 or by the palladium catalyzed Suzuki cross-coupling
reaction between a halogenated aniline and a suitably-substituted
arylboronic acid. In case the starting halogenated aniline is substituted
by a ciano group in the ortho position, the Suzuki cross-coupling
reaction is followed by the conversion of the cyano moiety to the
correspondent tetrazolyl or 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl
derivative, as described in Valgeirsson et al. in Journal of Medicinal
Chemistry 2004 47 (27) 6948-6957. As an example of the synthetic
experimental procedure for a non-commercial-aniline derivative B, the
synthesis of the intermediate D is reported.

[0124]A mixture of 4-amino-4'-chloro-biphenyl-3-carbonitrile (5.3 g, 1
eq), sodium azide (2.3 g, 1.5 eq) and trethylamine hydrochloride (4.9 g,
1.5 eq) is suspended in 40 ml of toluene and heated (60° C.)
overnight. To the reaction mixture, cooled to room temperature, water and
4M HCl are added, to afford the title compound as a white solid. This is
collected by filtration (4.83 g, 77% yield) and used for the next step
without further purification.

[0129]To a stirred solution of
4'-chloro-3-(1H-tetrazol-5-yl)-biphenyl-4-ylamine (0.40 g) in pyridine
(12 ml), a solution of the commercial 4-chlorophenylacetylchloride (0.28
g, 1 eq) is added portion-wise and stirring is continued overnight at
50° C. The resulting reaction mixture is evaporated to dryness and
the solid residue is washed first with HCl 1N and water, and then
purified by crystallization from ethanol/water (0.45 g, 72% yield).
LC-ESI-HRMS of [M-H]- shows 422.0561 Da. Calc. 422.057541 Da, dev. -3.4
ppm.

[0130]To a stirred solution of
4'-Fluoro-3-(1H-tetrazol-5-yl)-biphenyl-4-ylamine (0.337 g) in pyridine
(12 ml), a solution of commercial 4-chlorophenylacetylchloride (0.25 g, 1
eq) is added portion-wise and stirring is continued overnight at
50° C. The resulting reaction mixture is evaporated to dryness and
the solid residue is washed first with HCl 1N and water, and then
purified by crystallization from ethanol (0.46 g, 85% yield). LC-ESI-HRMS
of [M-H]- shows 406.0852 Da. Calc. 406.087091 Da, dev. -4.7 ppm

[0131]To a stirred solution of
4'-Amino-3'-(1H-tetrazol-5-yl)-biphenyl-4-sulfonic acid dimethylamide
(1.09 g) in pyridine (25 ml), a solution of the commercial
4-chlorophenylacetylchloride (0.6 g, 1 eq) is added portion-wise and
stirring is continued overnight at 50° C. The resulting reaction
mixture is evaporated to dryness and the solid residue is washed first
with HCl 1N and water, and then purified by crystallization from
ethanol/water (0.72 g, 48% yield). LC-ESI-HRMS of [M-H]- shows 495.1009
Da. Calc. 495.100613 Da, dev. 0.6 ppm.

[0132]To a stirred solution of
3-(1H-tetrazol-5-yl)-4'-trifluoromethoxy-biphenyl-4-ylamine (0.34 g) in
pyridine (10 ml), a solution of the commercial
4-chlorophenylacetylchloride (0.2 g, 1 eq) is added portion-wise and
stirring is continued overnight at 50° C. The resulting reaction
mixture is evaporated to dryness and the solid residue is washed first
with HCl 1N and water, and then purified by crystallization from ethanol
(0.32 g, 62% yield). LC-ESI-HRMS of [M-H]- shows 472.0779 Da. Calc.
472.078812 Da, dev. -1.9 ppm.

[0133]To a stirred solution of
3-(4-Amino-4'-trifluoromethyl-biphenyl-3-yl)-4H-[1,2,4]oxadiazol-5-one
(0.42 g) in pyridine (10 ml), a solution of commercial
2-(3,5-difluorophenyl)ethanoyl chloride (0.25 g, 1 eq) is added
portion-wise and stirring is continued overnight at 50° C. The
resulting reaction mixture is evaporated to dryness and the solid residue
is washed first with HCl 1N and water, and then purified by flash
chromatography using ethyl acetate (20%) and petroleum ether (80%) as
eluent, to afford the title compound as yellowish powder (0.16 g, 19%
yield). LC-ESI-HRMS of [M-H]- shows 474.0875 Da. Calc. 474.087707 Da,
dev. -0.4 ppm.

[0138]The electrical current through the BK channel is measured by
conventional two-electrode voltage clamp. BK current is activated by
repeated step protocols. In brief, this protocol goes from a resting
membrane potential of -40 mV lasting for 5 s to a depolarised step to +20
mV lasting for 1 s. The protocol was repeated continuously.

[0139]Having reached a stable current level, Compound A (3 μM) and
Compound B (10 μM), respectively, was added. A marked increase in the
current activated by depolarisation could be observed. The BK current
activity returned to baseline after approximately 30-80 seconds of wash.
In summary BK current was increased by 367±92% in the presence of 3
μM of Compound A (n=3, SD value), and 327±88% in the presence of 10
μM of Compound B.

[0140]The results are presented in FIG. 1.

Example 3

In Vitro Human Erythrocyte Chloride Conductance

[0141]In this example the chloride channel blocking activity of an
acetamide derivative representative of the invention, i.e. Compound 3
(2-(4-Chloro-phenyl)-N-[4'-chloro-3-(1H-tetrazol-5-yl)-biphenyl-4-yl]-ace-
tamide), has been determined.

[0142]All dose-response experiments were therefore performed by
concomitant measurements of conductive netfluxes of Cl.sup.- (JCl)
and membrane potentials (Vm) in suspensions of erythrocytes as
described by Bennekou et al. (Bennekou P and Christophersen P: Flux ratio
of Valinomycin--Mediated K+Fluxes across the Human Red Cell Membrane
in the presence of the Protronophore CCCP; J. Membrane Biol. 1986 93
221-227).

[0143]The membrane Cl-conductances (GCl) were calculated according to
Hodgkin et al. (Hodgkin A L and Huxley A F: The components of membrane
conductance in the giant axon of Loligo; J. Physiol. Lond. 1952 116
449-472) using the following equation:

G Cl = F * J Cl ( V m - E Cl ) ##EQU00001##

[0144]where F is the Faraday constant and ECl is the Nernst potential
for the Cl-ion.